Genetic and pharmacological disruption of vascular signaling pathways have provided unequivocal evidence that abnormal angiogenesis is a hallmark feature of cancer (Hanahan and Weinberg (2011); Chung and Ferrara, Annu. Rev. Cell Dev. Biol. 27, 563-584 (2011); Carmeliet and Jain, Nature 473, 298-307 (2011)). Cancer cells adapt to low oxygen tension by promoting the expression of genes associated with anaerobic metabolism, invasion and angiogenesis (Pugh et al., Nat. Med. 9, 677-684 (2003); Fraisl et al., Dev. Cell 16, 167-179 (2009)). The concerted action of hypoxia-regulated pathways allows tumor cells to sprout new vessels, co-opt host vessels and/or recruit angio-competent bone marrow-derived cells to generate functionally abnormal tumor vasculatures (Ferrara et al., Nature 438, 967-974 (2005)). Vascular endothelial growth factors (VEGFs) play central roles in this process through activation of VEGF receptor tyrosine kinases (RTKs), including VEGFR1 (Flt-1), VEGFR2 (KDR/Flk-1) and VEGFR3 (Flt-4), on endothelial cells (ECs) (Chung and Ferrara, Annu. Rev. Cell Dev. Biol. 27, 563-584 (2011)).
Blockade of VEGF-A signaling with BEVACIZUMAB, a humanized anti-VEGF monoclonal antibody (mAb) or with RTK inhibitors, such as SUNITINIB or SORAFENIB, has improved progression-free survival for patients with several types of cancers, including metastatic colorectal cancer, advanced non-small cell lung cancer, metastatic breast cancer, renal cell carcinoma and advanced hepatocarcinoma (Kerbel (2008); Ellis and Hicklin, Nat. Rev. Cancer, 8:8, 579-91 (2008)). However, although approved therapies targeting VEGF-A have offered considerable clinical benefit, many patients whose tumors initially responded eventually become non-responsive, suggesting the contribution of compensatory pathways that preserve angiogenesis in VEGF-targeted therapies (Bergers and Hanahan, Nat. Rev. Cancer 8:8, 592-603 (2008)). For tumors having evasive resistance or intrinsic refractoriness (“tumors refractory to anti-VEGF” or “anti-VEGF refractory tumors” herein), the approved therapies targeting VEGF-A fail to produce enduring clinical benefits.
There remains a need in the art for treating or inhibiting tumors that are refractory to conventional anti-VEGF treatments.